Collaborative Research: DMS/NIGMS 1: Mesoscale Kinetic Theory of Early Mitotic Spindle Organization

为了使生命增殖，细胞必须在细胞分裂时忠实地将其遗传物质平均地分裂成两个新的子细胞。高度动态的双极性有丝分裂纺锤体，由称为微管的蛋白质细丝构成，是完成这一基本任务所需的细胞机器。纺锤体装配过程中的错误与癌症等疾病有关。建立纺锤体的关键初始步骤包括形成纺锤极的复制中心体的分离。这涉及到结合微管并在微管上产生力的各种蛋白质。虽然机械的相互作用是复杂的，但相关因素的数量似乎足够小，以至于它们的集体作用可以用精确的生物物理术语来分析。该项目将结合生物物理实验室实验、计算物理模型和统计参数化框架，以详细了解纺锤体形成如何受到不同蛋白质成分相互作用的影响。在方法上，该研究旨在连贯地发展早期纺锤体形成的物理可解释的结构理论，该理论是自下而上建立的，具有复杂阶段之间的明确联系。此外，来自数学科学、生物学和物理学的研究团队将为大学和当地高中的学生开展教育推广活动，强调如何利用数学、物理学和生物学的协作方法来更好地理解生命科学的重要过程。该项目的关键技术创新将是中尺度动力学理论框架的构建。该框架将通过统计总结处理纺锤体和相关蛋白质浓度，并通过为本项目设计的体外实验配置在复杂性的增加阶段进行参数化。该理论模型将通过与计算模拟和新提出的体外实验的相互作用来发展，这些实验涉及具有简化几何形状的虚拟aster的微管束，用光学镊子探测。该项目将利用现有的粗颗粒动力学理论来模拟微管对与排列和非排列微管束之间的交联剂介导的相互作用。相对于非常详细的动力学理论和基于单个交联剂和微管的详细计算的直接模拟，将寻求一个简化的统计描述。该研究将确定并利用关键的集体变量，在调节和环境因素与由此产生的纺锤体动力学之间建立更易于计算和透明的联系，这有助于为未来的实验产生假设。分级复杂性集成过程将能够询问和纠正关于理解微管对的交联剂行为如何定量地扩展到微管束的物理假设。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

For life to proliferate, cells must faithfully divide their genetic material equally into two new daughter cells during cell division. The highly dynamic bipolar mitotic spindle, built from protein filaments called microtubules, is the cellular machine needed to accomplish this essential task. Errors in the spindle assembly process have been linked to diseases such as cancer. A critical initial step in building the spindle involves the separation of duplicated centrosomes that form the spindle poles. This involves a variety of proteins that bind and generate a force on the microtubules. While the mechanical interplay is complex, the relevant factors appear small enough in number that their collective action can be analyzed in precise biophysical terms. This project will combine biophysical laboratory experiments, computational physical models, and statistical parameterization frameworks in order to build detailed understanding of how spindle formation is affected by the interaction of the diverse protein components. Methodologically, the research aims to coherently evolve a physically interpretable structural theory of early spindle formation that is built bottom-up with clear linkages between stages of complexity. Additionally, the research team from mathematical sciences, biology, and physics will develop educational outreach activities for students at the universities and local high schools, emphasizing how collaborative methodologies from mathematics, physics, and biology can be deployed to better understand vital processes in the life sciences.The key technical novelty of this project will be the construction of a mesoscale kinetic theory framework. The framework will treat the spindle and associated protein concentrations through statistical summaries and be parameterized in increasing stages of complexity through in vitro experimental configurations designed for this project. The theoretical model will be developed through interaction with computational simulations and newly proposed in vitro experiments involving microtubule bundles with virtual asters in simplified geometries, probed by optical tweezers. The project will exploit the coarse-grains existing kinetic theory to model crosslinker-mediated interactions between pairs of microtubules to aligned and non-aligned bundles of microtubules. A reduced statistical description will be sought relative to highly detailed kinetic theories and direct simulation based on a detailed accounting of individual crosslinkers and microtubules. The research will identify and exploit key collective variables for a more computationally tractable and transparent connection between regulatory and environmental factors and the resulting spindle dynamics, which can aid in generating hypotheses for future experiments. The graded complexity integration process will enable interrogation of and corrections to physical assumptions regarding understanding how crosslinker behavior for microtubule pairs scales up quantitatively to microtubule bundles.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.